Preclinical development of a chimeric antigen receptor T cell therapy targeting FGFR4 in rhabdomyosarcoma

Area of Science:

• Oncology
• Immunotherapy
• Molecular Biology

Background:

• Relapsed or refractory rhabdomyosarcoma (RMS) in pediatric patients has poor cure rates, necessitating novel therapeutic strategies.
• Fibroblast growth factor receptor 4 (FGFR4), an oncogenic receptor tyrosine kinase, is highly expressed in RMS but minimally in healthy tissues, presenting a potential therapeutic target.

Purpose of the Study:

• To develop and evaluate a second-generation chimeric antigen receptor (CAR) T-cell therapy targeting FGFR4 for the treatment of rhabdomyosarcoma.
• To assess the in vitro and in vivo efficacy and selectivity of the FGFR4-targeting CAR T-cells.

Main Methods:

• Development of a second-generation CAR T-cell therapy (3A11 CAR T-cells) utilizing an anti-FGFR4 murine monoclonal antibody (3A11).
• In vitro assessment of 3A11 CAR T-cell activity, including cytokine production and cytotoxicity against RMS cell lines and healthy human primary cells.
• In vivo evaluation of 3A11 CAR T-cell persistence and anti-tumor efficacy in preclinical models of metastatic and orthotopic RMS.

Main Results:

• 3A11 CAR T-cells demonstrated robust cytokine production and potent cytotoxicity against RMS cell lines in vitro.
• The therapy exhibited high selectivity, with minimal activation against healthy human primary cells, confirming tumor-specific targeting.
• In vivo studies showed that 3A11 CAR T-cells were persistent and effectively eradicated RMS tumors in multiple preclinical models.

Conclusions:

• Chimeric antigen receptor T-cell therapy targeting fibroblast growth factor receptor 4 (FGFR4) is a promising therapeutic approach for rhabdomyosarcoma.
• The 3A11 CAR T-cell therapy demonstrated significant anti-tumor activity and selectivity, supporting its potential clinical application in patients with RMS.